Advances in the Evolutionary Understanding of MHC Polymorphism

Lots of buzz has been generated over sweaty T-shirt experiments, which suggest that humans can sense a potential mate’s major histocompatibility complex (MHC). But, questions remain on how variation in MHC genes arises and how this variation is maintained. MHC genes code for glycoproteins that bind peptides of invading pathogens and present them to natural killer cells (NK) and T-lymphocytes (T-cells). In a sense, these MHC-expressing cells, also known as antigen-presenting cells, catch a pathogen and show it to NKs and T-cells with the message “see this? find more and kill them!” This process is a critical component of the body’s adaptive immune response. One fascinating characteristic of MHC genes is their extreme polymorphism in the regions coding for the peptide-binding sites (PBS). PBSs contain the amino acid residues that interact with the antigen peptides. With more diversity in the PBSs, there is more potential to bind a diverse array of pathogens and therefore variation in PBSs is thought to be adaptive. The author of this review, Advances in the Evolutionary Understanding of MHC Polymorphism, discusses how pathogens influence frequency changes in MHC alleles and the selection processes that maintain the diversity at these loci.

One mechanism put forth to explain the maintenance of variation in MHC alleles is heterozygote advantage (HA), which states that an individual with variation in their MHCs can react to more pathogen types. Evidence demonstrates that heterozygosity in MHC alleles in some cases results in increased immunity to infection and therefore could play a role in maintaining diversity at these loci. Another mechanism considered important to driving the increase in variation of MHC alleles is negative frequency-dependent selection (NFDS), which states that pathogens will change over time to avoid the common MHC types. This leads to a coevolution scenario in which MHC alleles change over time as pathogens adapt to the common MHC types. Although these two mechanisms might explain in part the variation in MHC alleles observed, it is likely a combination of many selection processes work together to keep the high diversity in MHC alleles. 

Processes Shaping MHC Variation & Antigen-Binding Range

A. Pathogens change rapidly over short periods of time, which results in the reduced fitness of common MHC alleles, and increases the potential fitness of rarer or novel MHC alleles

B. HA occurs when differing MHC alleles in an individual increase immunity to different pathogens

Link to Paper: https://www.cell.com/trends/genetics/fulltext/S0168-9525(20)30021-4

Elaine Miller – Trends in Genetics Post 2